Summary In the heart, as in cancer, metabolism provides energy and building blocks for the cell. James Watson (of The Double Helix fame) recently pronounced that in cancer, targeting metabolism may be a more promising approach to treatment than targeting transforming genes. At a time when cellular regeneration receives much attention, the intracellular dynamics of metabolism must be considered as well. In earlier work supported by this grant, we identified two metabolic signals serving as regulators of protein turnover in the heart: a low [ATP] / [AMP] ratio as regulator for protein degradation, and glucose 6-phosphate as regulator of the mTOR growth signaling pathway. We learned that in the heart, like in cancer cells, a phenomenon known as the Warburg Effect drives metabolic rearrangements which are linked to enable cell growth. Perhaps even more importantly, we learned that the oncometabolite D-2-hydroxyglutarate impairs cardiac function by inhibiting a Krebs cycle enzyme. Our overall objective is now to solidify the concept of a link between cancer cell metabolism, and cardiac cell metabolism, cardiac structure, and cardiac function independently from any chemotherapeutic agents or pharmacological interventions. Specific Aim 1 will define the role of oncometabolic signals as regulators of cardiac remodeling. Specific Aim 2 will define the role of reductive carboxylation as a mediator for metabolic structural and functional remodeling of the heart using the oncometabolite D-2-hydroxyglutarate as a model. Specific Aim 3 will extend the findings to address specific structural, proteomic and epigenetic mechanisms of remodeling in the metabolically deregulated state of D-2- hydroxyglutarate. In summary, as we continue our work on the intracellular self-renewal of the cardiomyocyte, we expect to identify new regulatory proteins and enzymes that drive adaptation to metabolic stress in the heart. Our long-term goal is to develop a platform for new metabolic strategies to support the failing human heart by integrating specific, dynamic aspects of cancer cell metabolism with heart metabolism. In short, metabolic systems do not exist in isolation and their understanding may be exploited for the treatment of heart failure.